Lymphoma 101. Nathalie Johnson, MDPhD. Division of Hematology Jewish General Hospital Associate Professor of Medicine, McGill University

Transcription

1 Lymphoma 101 Nathalie Johnson, MDPhD Division of Hematology Jewish General Hospital Associate Professor of Medicine, McGill University

2 Disclosures Consultant and Advisory boards for multiple companies that make novel drugs Roche Abbvie Gilead Jansson Lundbeck Merck Research funding (Roche, Abbvie, Lundbeck)

3 Outline Genetics of cancer Lymphoma subtypes Lymphoma treatments Novel therapies

4 Cancer = uncontrolled cell growth of clones that are genetically different than normal cells

5 Growth is controlled by genes, made of DNA

6 Genes control all functions of the cell

7 DNA damage can cause loss of growth control or prevent the cell from dying

8 Function of the Lymphatic System To defend the body against intruders

9 Lymphocytes B-cells develop in the bone marrow form antibodies against foreign bodies T-cells develop and mature in the thymus gland orchestrate the immune response NK (natural killer) cells destroy viruses and cancers through direct attack

10 Lymphomas arise from normal lymphocytes at different stages of maturation Bone Marrow Lymph node B cell progenitor acquire CD20 BCR Immature B cell CLL A N T I G E N T centroblasts FDC Clonal expansion Differentiation (high-affinity BCR) T centrocytes Memory B cell Plasma cell Apoptosis low-affinity BCR Most common lymphomas occur in the germinal center: DLBCL, Follicular Hodgkin and Burkitt lymphomas CLL

11 Lymphoma types Non-Hodgkin (NHL) 85-90% of all lymphomas ~50 subtypes Indolent vs aggressive variants Hodgkin (HL) 10-15% of all lymphoma High cure rate

12 Hodgkin Lymphoma 1000 cases/year in Canada Two peaks: young adults and elderly Can be difficult to diagnose Cancer cells represent 1% of cells in the biopsy > 80% curable with chemotherapy +/- radiation Normal HL

13 Indolent Non-Hodgkin Lymphomas 8200 cases per year in Canada: multiple subtypes Follicular lymphoma and CLL most common Less common: marginal zone lymphoma, mantle cell lymphoma, lymphoplasmocytic lymphoma Slow evolution, recurrent, unlikely curable Asymptomatic patients usually do not require treatment, but active monitoring Normal Follicular lymphoma CLL

14 Aggressive Non-Hodgkin Lymphomas Diffuse large B-cell lymphoma Most common lymphoma 35-40% of cases of NHL Often curable (65%) Very aggressive (e.g. Burkitt, lymphoblastic) Often curable (>80%)(leukemia-like treatment) DLBCL Burkitt Lymphoblastic

15 Signs and symptoms of lymphoma History: Fatigue Lumps/bumps Shortness of breath, abdominal pain/symptoms Rash or itching Constitutional ( B ) symptoms: - Fever - Drenching Night Sweats - Weight loss (>10% of baseline weight)

16 Evaluation of the lymphoma patient Examination of tumor sample (biopsy) Evaluation of spread (staging) CT scans PET scan +/- Bone marrow biopsy Know the patient State of health Psychological state Determination to fight Support network

17 Staging of lymphoma A: absence of B symptoms B: presence of fever, night sweats, weight loss

18 Treatment Most important is to establish goal of treatment Curative intent versus a prolonged remission versus symptom control

19 Factors affecting treatment Type of lymphoma Age Functional status Comorbidities (other diseases) Disease stage and bulkiness Prior therapies

20 Lymphoma treatment: generally not surgery Usually only indicated for diagnostic purposes (biopsy), not as a means of definitive treatment

21 Observation for indolent lymphomas Watch and wait (watch and worry?) recommended for individuals without symptoms or organ compromise Many indolent lymphomas will never progress to a point where treatment becomes necessary Overall survival does not appear to be worse for patients whose inhl is initially observed (vs treated at the time of diagnosis, even in the absence of symptoms)

22 Lymphoma treatment: radiotherapy Lymphomas that have limited spread can sometimes be treated (and even cured) by radiation alone

23 Lymphoma treatment: chemotherapy Lymphoma that has spread within the body, or is aggressive in nature, is usually treated with chemo(immuno)therapy

24 Chemotherapy regimens for lymphoma developed after World War II Mustard Gas in WWII Veterans exposed to mustard gas had decreased white blood cell counts 1965: MOPP (before ABVD and CHOP) M: nitrogen mustard (mechlorethamine) O: oncovin PP: prednisone and procarbazine Side effects: ++ nausea, sterility, leukemia 1975: ABVD in Hodgkin Lymphoma Adriamycin (cardiac toxicity) Bleomycin (lung and skin toxicity ~3%) Vinblastine (neuro toxicity) Dacarbazine (nausea, pain) 1976: CHOP in non-hodgkin lymphoma Cyclophosphamide, hydroxyrubicin, oncovin, prednisone Cardiac, neuro, nausea, leukemias (2%)

25 Advanced Stage Hodgkin > 80 % are cured with ABVD Survival at 7 years = 84% (ABVD) 89% (BEACOPP), p>0.05 Thus need to minimize toxicities for survivors Viviani et al. NEJM 2011

26 CHOP the standard chemotherapy backbone for DLBCL: cured 40% of patients Fisher et al. NEJM 1993, 328:

27 Success of immunotherapy in DLBCL: Rituximab-CHOP standard of care Rituximab: antibody targeting the CD20 protein on B cells R-CHOP is better than CHOP ~50% improvement in survival Rituximab binds to lymphoma cells which will be targeted for destruction by other immune cells Coiffier et al. NEJM 2002, 328:

28 Follicular lymphoma Prima trial: RCHOP x 6 cycles followed by 2 years of rituximab maintenance STiL trial: Bendamustine and rituximab (BR) x 6 cycles no rituximab maintenance

29 Efficacy The Balance Between Efficacy and Safety in Front Line CLL FCR 4.5 y BR 3.5 y Ob-Clb ~2.5y Progression free survival R-Clb ~1.5y Toxicity FCR 76-91% BR 79% Owen C, et al. Clin Lymphoma Myeloma Leuk. 2015;15(6): % Grade 3 + adverse events Ob-Clb 73% R-Clb 50-56% FR, fludarabine + rituximab; FC, fludarabine + cyclophosphamide; Ob-Clb, obinutuzumab + chlorambucil; R-Clb, rituximab + chlorambucil.

30 Life after primary chemotherapy What is response? PET scan Progression Biopsy, salvage chemo and transplant Stable disease Residual PET avid nodes within Partial response a radiation field may get radiation therapy Complete response No further therapy or scans Monitoring patients in remission: most relapses occur < 2 years of completing chemotherapy (20-40% Hodgkin and 25-50% DLBCL) every 3 months x 2 years, then every 6 months x 3 years then every year to monitor for relapse and long term toxicity No pregnancies within first 2 years Goal: return to normal Issues: Anxiety, Depression, Fatigue

31 New cancer treatments: monoclonal antibodies Antibodies developed against cancer cells can be administered to patients to destroy the tumor Examples: CD20: Obinutuzumab and Ofatumumab CD52: Alemtuzumab CD30: Brentuximab vedotin Samantha M. Jaglowski et al. Blood 2010;116:

32 Stem cell transplantation (SCT) When lymphoma can no longer be managed by conventional chemotherapy, it can sometimes be controlled or cured through high dose chemo and stem cell rescue Rarely, allogeneic stem cell transplants may be employed

33 Lymphoma treatment: the designer drugs Drugs are being developed to interfere specifically with the abnormal gene products of cancer cells with minimal effect on normal cells, e.g.: Ibrutinib (CLL, relapsed MCL) Idelalisib (relapsed CLL, relapsed inhl) Venetoclax (relapsed CLL)

34 Ibrutinib mechanism of action

35 Resonate: Ibrutinib is superior to ofatumumab in terms of progression free survival and overall survival in patients with relapsed CLL Byrd et al. NEJM 2014 Overall response: 40% Ibru vs 4% Ofa No difference in response based on 17p del status

36 Ibrutinib for front-line CLL 84% reduction in risk of progression or death with Ibrutinib Burget et al. NEJM month PFS rate: 90% with Ibrutinib vs. 52% with Chlorambucil

37 Idelalisib targets PI3Kd in CLL (and normal B & T cells)

38 Idelalisib & rituximab is superior to rituximab At 24 weeks, disease progression occurred in 12 patients (10.9%) with Zydelig + rituximab vs 53 patients (48.2%) with placebo 1

39 Venetoclax kills CLL cells that are primed to die Concept by Antony Letai

40 Venetoclax induces rapid clearance of peripheral blood lymphocytes Stilgenbauer et al. Lancet Oncol Jun;17(6):768-78

41 Venetoclax and rituximab in relapsed CLL Murano trial, NEJM 2018

42 Lymphoma treatment: immunotherapy Drugs that activate the immune system to kill lymphoma cells e.g.: PD1 inhibitors for Hodgkin lymphoma CAR-T cells for DLBCL

43 Immune checkpoint inhibitors PD-L1/2 is highly expressed on some tumor cells Binding of T-cells to PD- L1/2 inhibits T-cell function and blunts the normal immune response PD-1 inhibitors have been shown to be very effective in relapsed HL, among other cancer types

44 Immunotherapy with PD1 inhibitors: 70% response in relapsed Hodgkin lymphoma Ansell et al. NEJM 2015

45 Experimental therapy: chimeric antigen receptor gene therapy

46 Summary: frontline therapies used in 2019 Diffuse large B-cell lymphoma (curative) R-CHOP Hodgkin Lymphoma (curative) ABVD inhl (Follicular lymphoma) (prolonged remission) R-CVP or RCHOP followed by maintenance R R-Bendamustine +/- maintenance R Chronic Lympocytic leukemia (prolonged remission) FCR R-Bendamustine Obinutuzumab and chlorambucil Ibrutinib likely will be approved frontline for everyone based on recent data

47 Novel therapies Ibrutinib (CLL, MZL, LPL) Idelalisib (CLL and FL) Venetoclax (CLL) Immunotherapies: PD1 inhibitors (Hodgkin) and CAR-T (DLBCL)

48 Side effects of novel therapies Ibrutinib Neutropenia Cardiac Arrythmias Bleeding Idelalisib Opportunistic infections Colitis/diarrhea Venetoclax Neutropenia Nausea Tumor lysis Immunotherapies: Autoimmune side effects Neurological and cytokine release syndrome with CART-T Advantage: oral medications, kills cells in a different way than chemotherapy Disadvantages: Some have low complete responses use indefinitely until progression Cost (~$8,000 to 12,000/month and ~$~500,000 for CAR-T)

49 Conclusion Lymphomas constitute a large group of disorders having highly variable natural histories, treatments and outcomes Almost all lymphomas are treatable Many lymphomas are curable Research allows us to continuously expand treatment options, with the goal of improving treatment outcomes and quality of life

50 Questions?